Osteoporosis affects 55% of Americans over the age of 50, and incurs a medical cost of $47 million a day. It is caused by a disruption in the fine equilibrium between bone resorption and bone deposition. Currently, the most successful pharmaceutical drugs for osteoporosis target bone resorption only, i.e. Oestrogen Therapy & Bisphosphonates. Bone deposition, on the other hand, is now known to be under the control of the WNT pathway co-receptor LRP5. The human high bone mass trait results from a G171V point mutation in LRP5, whereas, the LRP5 loss of function syndrome, OPPG, causes low bone mass. We have isolated a novel secreted molecule, termed Wise, which shares homology with a known human bone density regulator, SOST/Sclerostin. Deficiency of SOST in humans leads to a skeletal disorder characterized by increased bone density due to hyperactive osteoblasts and gain of SOST function in mice leads to a low bone mass phenotype. We have evidence that a deficiency of Wise in mice, as in humans with SOST, leads to an increase in bone density. Others speculate that this effect on bone density is working through inhibition of the Bone Morphogenesis Protein (BMP) pathway. However, we have evidence that Wise and SOST function to modulate bone density by binding to the WNT co-receptor LRP5 but not to LRP5 G171V and inhibiting the WNT pathway in osteoblasts. In vivo studies have shown that pharmacological inhibition of Sost results in increased bone mass with normal bone lamellar structure, serum chemistry, and hematological panels indicate no systemic abnormalities. The goal of Phase I am to identify small organic molecules that neutralize SOST function and increase bone density and quality. We have developed proprietary assays to identify small molecules that block the interaction between SOST and LRP5/6, thus neutralizing SOST function. We have tested our assays and have found them to be effective in identifying specific molecules capable of blocking SOST binding to LRP5/6. We plan to screen a hand picked small molecule library. In Phase II, we will authenticate our positive high throughput hits for specificity of SOST/LRP interaction, and establish/conclude preclinical efficacy of authenticated small molecules. [unreadable] [unreadable] [unreadable] [unreadable]